Interferon (IFN) pretreatment of low-passage mouse embryonic fibroblasts (MEF) infected with lymphocytic choriomeningitis virus or vaccinia virus rendered these cells two to three times more susceptible to lysis by H-2 restricted, virus-specific cytotoxic T lymphocytes (CTL) than control, virus-infected MEF. The increased sensitivity to lysis correlated with increased expression of surface H-2 antigens, but not viral antigens. Continuous cell lines already highly sensitive to CTL-mediated lysis and already expressing high levels of surface H-2 antigens were unaffected by IFN pretreatment. These results suggest that IFN treatment, by increasing surface H-2 levels, may result in increased association of surface H-2 and virus antigens, leading to enhanced recognition and lysis by virus-specific CTL.